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J. Biol. Chem., Vol. 283, Issue 35, 23914-23921, August 29, 2008

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Analgesic Compound from Sea Anemone Heteractis crispa Is the First Polypeptide Inhibitor of Vanilloid Receptor 1 (TRPV1)^*

Yaroslav A. Andreev¹, Sergey A. Kozlov, Sergey G. Koshelev, Ekaterina A. Ivanova, Margarita M. Monastyrnaya, Emma P. Kozlovskaya, and Eugene V. Grishin

From the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, 117997 Moscow and the Pacific Institute of Bioorganic Chemistry of the Far Eastern Branch of the Russian Academy of Sciences, 690022, pr. 100 let Vladivostoku, 159, Russia

Venomous animals from distinct phyla such as spiders, scorpions, snakes, cone snails, or sea anemones produce small toxic proteins interacting with a variety of cell targets. Their bites often cause pain. One of the ways of pain generation is the activation of TRPV1 channels. Screening of 30 different venoms from spiders and sea anemones for modulation of TRPV1 activity revealed inhibitors in tropical sea anemone Heteractis crispa venom. Several separation steps resulted in isolation of an inhibiting compound. This is a 56-residue-long polypeptide named APHC1 that has a Bos taurus trypsin inhibitor (BPTI)/Kunitz-type fold, mostly represented by serine protease inhibitors and ion channel blockers. APHC1 acted as a partial antagonist of capsaicin-induced currents (32 ± 9% inhibition) with half-maximal effective concentration (EC₅₀) 54 ± 4 nM. In vivo, a 0.1 mg/kg dose of APHC1 significantly prolonged tail-flick latency and reduced capsaicin-induced acute pain. Therefore, our results can make an important contribution to the research into molecular mechanisms of TRPV1 modulation and help to solve the problem of overactivity of this receptor during a number of pathological processes in the organism.

Received for publication, January 30, 2008 , and in revised form, June 11, 2008.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AM933240.

^* This work was supported by the Russian Federation Federal Agency for Science and Innovations (the State Contract 02.467.11.3003 of 20.04.2005), the Russian Foundation for Basic Research, and the Cellular and Molecular Biology program of Russian Academy of Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 7495-336-40-22; Fax: 7495-330-7301; E-mail: ay{at}land.ru.

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